The sense of touch is unique in perceiving stimuli both physical (temperature, mechanical) and chemical (compounds that cause pain, itch, et cetera) in nature. In each modality, touch neurons distinguish noxious (painful) from innocuous stimuli, and the sensitization of touch neurons in response to injury and inflammation is the basis for many clinically-relevant chronic pain states. Discovery of the Transient Receptor Potential (TRP) ion channel sensors for temperature has advanced our understanding of thermosensation. However, recent data suggests that thermoTRPs are unlikely to explain all of the thermosensory capability of the somatosensory or other temperature-dependent systems. We have very recently identified components of a mechanically-activated cation channels named Piezos. Piezo2 can account for rapidly-adapting but not slowly-adapting mechanically-activated currents in DRGs. Indeed, mechanosensation remains perhaps the least understood of the mammalian sensory receptor systems. Therefore, the molecular identities of thermosensitive (TS) and mechanosensitive (MS) ion channels and proteins in mammals have been elusive, and the cloning and characterization of these sensors will provide a critical foundation for the study of pain perception and pain relief. Our proposal uses state-of-the-art technologies of screening candidate- and genome-wide full length cDNAs and RNAis to identify novel receptors and potential sensors. PUBLIC HEALTH RELEVANCE: The molecules that mediate detection of touch stimuli have been a long-standing mystery. We do not know the identity of most of the ion channels that sense mechanical force, and only some of the temperature-sensors are identified. We will use genomic screens to find novel proteins that are directly/indirectly activated by temperature and pressure.